The major complications of rejection and infection following allotransplantation underscore the need to develop methods which will enable a more specific manipulation of the human alloimmune response. Future efforts directed toward this goal would be aided by a better understanding of the immunological factors related to allograft survival and rejection in man. The proposed research is designed to: 1) Study immunological mechanisms (tolerance, suppressor T cells, anti-donor blocking anitbody, anti-idiotype antibody) involved in the inability of a selected population of long-term renal allograft recipients to generate cytotoxic T cells against HLA non-identical donor cells, while generating a normal response against unrelated cells. 2) To carry out longitudinal studies in renal transplant recipients pre- and early post-transplant to determine whether in vitro patterns of specific cell-mediated alloimmune responsiveness and serum blocking factors can be related to clinical allograft non-reactivity. 3) To examine the hypothesis generated by preliminary experiments in our laboratory that antibody-dependent cell-mediated cytotoxicity (ADCMC) is related to the clinical syndrome of chronic renal allograft rejection, which is currently the largest cause of graft loss in our experience. Experiments are designed to utilize related donor and indifferent lymphocytes to measure afferent alloimmune responsiveness in direct T cell cytotoxicity and in vitrol generated T cell cytotoxicity (CML), and antibody-dependent cell-mediated cytotoxicity. Recipient serum will be studied for presence of blocking factors in MLC and CML, and the specificity will be demonstrated. In addition, recipient lymphocytes will be studied for suppressor T cell activity. Clinical parameters of longitudinal rejection profile and current status of renal function will be considered in relation to data obtained in the in vitro assays.